The formation of carbon-carbon double bonds represents one of the pillars on which modern synthetic chemistry is based because the production of many natural products and drugs necessitate their assembly. Consequently numerous processes for the construction of carbon-carbon double bonds have been developed. Besides direct elimination, there are currently four reliable methodologies for the routine formation of alkenes: the Wittig, Peterson, and Kocienski-Julia olefination reactions, as well as metathesis. Currently only metathesis is catalytic and even this is limited in requiring alkene starting materials, with high loading of a suitably ligated transition metal catalyst, usually Ru or Mo, often required and, in the case of ring closing metathesis, high dilution. The use of transition metals may lead to complications in that any transition metal must be removed or substantially reduced for any products intended to be used as active pharmaceutical agents, for example.
In addition, environmental concerns increasingly influence decision making insofar as chemical synthetic route selection, which is impacted by the waste and energy consumption profile of a particular process. The Wittig reaction, for example, which is the most widely employed olefination process, comes at a cost—the stoichiometric formation of phosphine oxide byproduct.
Therefore the development of new eco-friendly catalytic methodology, which either limits the generation of waste or downgrades the waste produced, for example from toxic to harmful, would be highly desirable. The successful design and implementation of organocatalytic processes offers the possibility of lessening the environmental footprint that chemical industries have on their surrounding ecology. Therefore, an organocatalytic methodology that yields the possibility to construct olefins selectively would represent an important advance.
Of the three stoichiometric olefination processes mentioned above, the only one that may offer the realistic possibility to transition from a stoichiometric to a catalytic process, coupled with the selective formation of either E or Z alkenes, is the Wittig reaction. The Wittig reaction was discovered in 1953 by Georg Wittig and involves the treatment of an aldehyde or ketone with a phosphonium ylide, which yields an alkene concomitant with the generation of a phosphine oxide. Wittig's pioneering studies in this area resulted in his receipt of the 1979 Noble Prize for Chemistry. Since its discovery, the Wittig reaction has been used extensively, demonstrated by its inclusion in numerous natural product syntheses and undergraduate laboratory courses and teaching texts.
FIG. 1 illustrates a prior art textbook illustration for the Wittig reaction. The accepted mechanism involves the attack of a phosphonium ylide on an aldehyde or ketone, yielding an oxaphosphetane intermediate. Formation of the oxaphosphetane can occur through a direct [2+2] cyclo-addition reaction between the phosphonium ylide and the carbonyl compound. Alternatively it has been proposed that a betaine intermediate is first formed. The oxaphosphetane intermediate subsequently collapses via a retro-[2+2] cyclo-addition reaction to produce the desired alkene concomitant with phosphine oxide byproduct. Further discussion of the Wittig reaction can be found in O'Brien et al., Angew. Chem. Int. Ed. 2009, 48, 6836-6839 and references cited therein.
Although there has been significant work directed towards the development of the Wittig reaction, significant problems still persist and remain to be addressed. For one thing, the process is stoichiometric and for another, complete removal of the phosphine oxide byproduct is at best time consuming or is impossible. In some cases also, Wittig reactions give diastereomeric mixtures with ensuing purification issues. A catalytic protocol would reduce the amount of the phosphine oxide byproduct. The lack of a catalytic protocol also removes from serious consideration the possibility to control the olefination by alteration of the phosphine's structure. This is unfortunate, as the phosphine's structure has been shown to have a substantial impact on the stereochemical outcome of the reaction, and therefore a carefully designed phosphine may yield a selective process.
That said, the barriers to the development of a catalytic Wittig reaction are formidable, and the successful construction of a catalytic process relies on the completion of four steps: A) formation of the phosphonium ylide precursor, typically a phosphonium salt; B) generation of the phosphonium ylide, normally by deprotonation; C) olefination with concomitant generation of phosphine oxide; and D) reduction of the phosphine oxide byproduct producing phosphine to reenter the catalytic cycle. The most daunting of the aforementioned processes is step D—the required chemoselective reduction of the phosphine oxide byproduct to a phosphine in the presence of either an aldehyde or ketone starting material and alkene product.
One could ameliorate this problem of chemoselective reduction by the replacement of phosphorus with arsenic, tellurium, or antimony, as their corresponding oxides, owing to bond strength, are appreciably easier to reduce. In fact, such an approach has led to the successful development of catalytic Wittig-type processes employing arsines and tellurides (For a review on catalytic aldehyde olefinations see F. E. Kuhn, A. M. Santos, Mini-Rev. Org. Chem. 2004, 1, 55-64). Unfortunately, significant drawbacks to the broad adoption of the aforementioned methodologies are the intrinsic high toxicity and carcinogenicity of arsenic, tellurium, and antimony compounds; environmental contamination particularly of groundwater would be one concern if these reactions were performed on a large scale. Importantly, the catalytic use of phosphine would not suffer from these issues; therefore a Wittig reaction catalytic in phosphine would find wider employment. Furthermore, this would marry the power of the Wittig olefination protocol to the synthetic benefits of a catalytic reaction without the poisoning issues that can plague transition metal catalyzed processes.
This aforementioned reduction of phosphine oxide to phosphine is pivotal to the successful development of any catalytic Wittig process; therefore the available methodology to effect this reduction merits a detailed discussion. To date the most successful class of reagents for the reduction of phosphine oxides to phosphines is silanes. Other methodologies exist but none have the scope and reliability of silanes. Fritzsche and co-workers first reported the reduction of phosphine oxides with silanes in 1964 (Fritzsche, H. et al., Reduction of organic compounds of pentavalent phosphorus to phosphines. I. Reduction of tertiary phosphine oxides to tertiary phosphines with silanes. Chem. Ber. 1964, 97, 1988-1993; Fritzsche, H. et al., Reduction of organic compounds with pentavalent phosphorus to phosphines. Reduction of tertiary phosphine oxides to tertiary phosphines with trichlorosilane. Chem. Ber. 1965, 98, 171-174; Fritzsche, H. et al., Reduction of organic compounds of pentavalent phosphorus to phosphines. III. Preparation of primary and secondary phosphines with silanes. Chem. Ber. 1965, 98, 1681-1687).
These publications are a thorough evaluation of silane reducing agents, and four successful reducing agents emerged: phenylsilane, diphenylsilane, triphenylsilane, and trichlorosilane. Since Fritzsche's work, phenylsilane and trichlorosilane have emerged as the most widely utilized with the latter, often coupled with an amine base, the most employed.
The mechanism of reduction is dependent on the silane, and in the case of trichlorosilane in the presence of an amine often leads to inversion of the phosphorus center, while with phenylsilane reduction is achieved with retention.
Efforts towards the development of catalytic processes in the Wittig reaction have primarily focused on two main areas: 1) catalytic generation of the phosphonium ylide or 2) substitution of phosphorous by arsenic due to the reduction of the arsenic-oxygen bond being more easily achieved than the analogous phosphorus-oxygen bond. However, neither represents a true catalytic Wittig reaction, as this would necessitate the catalytic use of phosphine. Indeed, the only documented use of catalytic phosphine was disclosed for the related aza-Wittig reaction; however, the reduction protocol, an isocyanate, cannot be utilized in the parent reaction. Therefore, the development of a catalytic Wittig reaction where the phosphine is the catalytic species has not before been achieved.
The Mitsunobu reaction also utilizes a phosphine, in the conversion of primary and secondary alcohols to esters, phenyl ethers, thioethers, and various other compounds. The general mechanism is shown in FIG. 7. Discovered in 1967 by Professor Oyo Mitsunobu, the reaction is extensively employed in academic and industrial laboratories due to its scope, stereospecificity, and mild reaction conditions. The Mitsunobu reaction, like the Wittig, employs a phosphine and produces a phosphine oxide as a byproduct. Like the Wittig reaction, the Mitsunobu reaction often suffers from problems related to product isolation and purification. These issues occur due to the formation of phosphine oxide and hydrazine byproducts.
There are three possible ways the Mitsunobu reaction can be made catalytic: in phosphine, in hydrazine, and in both. FIG. 8 illustrates a Mitsunobu reaction cycle catalytic in phosphine. The most challenging protocol to develop would be the duel catalytic protocol, which would necessitate a reducing agent (phosphine oxide to phosphine) and an oxidizing agent (hydrazine to azo compound) being present in the same flask.